Epidemic keratoconjunctivitis (EKC) is a serious and contagious eye infection affecting both the conjunctiva and cornea and is caused by adenoviruses of type D, predominantly of serotypes 8, 19, 37. More than 50 serotypes of adenovirus have been isolated, and at least 19 documented serotypes cause eye infection. The most commonly associated serotypes that cause EKC include adenovirus 8, 19, and 37, and less frequently and in less severe forms, serotypes 2-5, 7, 9, 10, 11, 14, 16, 21, and 29. Because of low levels of natural immunity against adenovirus in the general population, i.e. adenovirus type 8 antibodies are found in less than 5% of the general population in the US, every individual is considered susceptible to infection.
EKC is characterized by typical symptoms of conjunctivitis such as acute onset of watering redness, foreign body sensation and severe pain. Symptoms further include inflammation in the conjunctiva (conjunctivitis) and in the cornea (keratitis), associated pain, edema, diminished eyesight, tearing, sensitivity to light, feeling or sensation as if a foreign body were present in the eye, and the development of pseudo membranes. During the acute phase, which persists for approximately two to three weeks, viruses are present and are replicating. In the typical case, first one eye gets infected after which the infection spreads to the other eye within two to three days. Both eyes are affected in 60% of cases. The infection in the first eye is typically more serious. In approximately 20-50% of patients, corneal opacities are developed that result in deteriorating vision that remains for weeks and months, and in rare cases even years. Since the disease is often epidemic in nature, it is called epidemic keratoconjunctivitis (EKC). Adenovirus conjunctivitis is a reportable infection in Germany (see e.g., Meyer-Rüsenberg et al., Dtsch Arztebl Int 2011; 108(27): 475-80) and is listed as a category IV infectious disease by Japan's National Epidemiological Surveillance of Infectious Diseases (NESID) with mandated collection, analysis and publication of reports on occurrences.
EKC still lacks an effective treatment, hence there is a large unmet medical need. Povidone-iodine eye drops seem to have only limited efficacy and at the same time cause an additional stinging sensation in the inflamed eyes and sometimes even discoloration of the conjunctiva. A more compatible pharmaceutical composition that could be used for the treatment of EKC and for the prevention of its spread would thus be highly desirable for patients suffering from the disease, as well as for individuals that come into contact with such patients such as relatives, friends, colleagues, physicians.
Unlike other influenza virus subtypes that cause predominant respiratory disease in humans, H7 influenza virus infections frequently result in ocular rather than respiratory symptoms (Belser et al., Emerg Infect Dis. 2009; 15:859-865). Therefore it is highly desirable that an antiviral formulation designed for the treatment of viral eye infections is effective during outbreaks of influenza resulting in ocular disease.
The use of carrageenans as excipients and viscosifiers in ophthalmology is well established. U.S. Pat. No. 5,403,841 describes carrageenan-based solutions that are useful for preparing eye drop formulations of pharmaceutically active ingredients. On contact with the tear film the solutions form a gel which maintains extended contact with the conjunctiva, preventing quick removal of the active principle from the eye surface and facilitating its topical delivery. For an extensive review of ophthalmic in situ gelling systems based on carrageenans or other charged polymers see e.g. Rupenthal et al., Int J Pharm. 2011; 411(1-2): 69-77 and 78-85. Polymeric systems containing carrageenan are also useful for trans-scleral delivery of macromolecular agents (Thrimawithana et al., Eur J Pharm Sci. 2011; 44(3):399-409). No intrinsic pharmaceutical activity of carrageenans is mentioned or implied in any of the above-mentioned documents.
Some ocular pharmaceutical preparations that employ carrageenans as excipients and/or mucomimetics contain antiviral agents. For example, international patent application WO 2007/039201 claims photo stable formulations of brivudine to treat herpetic keratitis. It is also known that carrageenans and related anionic polymeric mucomimetics can be used in solutions intended for cleaning and storage of contact lenses, where they improve the astringent properties of said solutions which contain low molecular weight agents with broad antimicrobial activity such as hydrogen peroxide, borate, or cetylpyridinium chloride (see WO 2009/152028 and WO 2010/038129). No antiviral or anti-inflammatory action is attributed to the carrageenan component of these solutions.
Ophthalmic preparations based on natural organic polymers are known to have been designed explicitly for treating conjunctival inflammation. For example, international patent application WO 2005/046562 claims sulfated hyaluronic acids for such a therapeutic purpose. Carrageenans are not mentioned in this disclosure.
Stiles et al. (Invest Ophthalmol Vis Sci 2008; 49(4): 1496-1501) report that treatment of cats suffering from experimentally induced herpetic conjunctivitis with an ocular preparation of lambda-carrageenan reduced the duration of the animal's infectivity, although the clinical course of the conjunctivitis was not shortened. This paper addresses only conjunctival inflammation caused by feline herpes virus; adenoviruses and carrageenans other than those of the lambda class are not mentioned.
In WO 2009/027057 an antiviral effect of iota-carrageenan against B-type (respiratory) adenoviruses was disclosed. In the same application it has been mentioned, however, that no significant effect against subtypes A, C, and D could be determined.